功能性碳纳米管的制备及其在活体内组织分布和代谢的初步研究
摘要
目的:制备表面带有氨基的功能性碳纳米管,用放射性同位素99mTc标记后对其在动物活体内的代谢和组织器官分布特征进行初步研究。
方法:
1.以多壁碳纳米管为原料,通过羧化、酰氯化进而与对苯二胺反应,得到表面有氨基的功能性多壁碳纳米管(MWNT-NH2),对反应前后原料及产物进行红外和Raman光谱分析。
2.将制得的MWNT-NH2与不同比例的二乙烯三胺五乙酸(DTPA)酸酐进行酰胺反应,通过酰胺键共价结合后,得到DTPA修饰的碳纳米管(MWNT-DTPA)并对产物行高分辨电镜、热失重和变温磁共振分析。
3.以蒸馏水溶解MWNT-DTPA,0.01%氯化亚锡(SnCl2)为还原剂,通过螯合作用将99mTc结合在MWNT-DTPA表面,并对产物MWNT-DTPA-99mTc行高分辨电镜及元素能谱分析。
4.以常规DTPA针剂用药为对照组,经耳缘静脉向家兔体内注射MWNT-DTPA-99mTc复合物溶液,同时使用单光子发射计算机断层成像系统(SPECT)扫描,观察其在家兔活体内的代谢及分布情况,随后穿刺膀胱抽取尿液进行电镜分析。
5.进行定量研究时,选取20只家兔随机分为4组,每组5只,麻醉后经耳缘静脉注入1ml配置好的MWNT-DTPA-99mTc复合物溶液,放射性强度0.5mCi。分别在注药物后0.5h、1h、2h和3h将四组家兔处死,取肺、心脏、肝脏、脾、双肾脏和膀胱(含尿)等器官称重,在每种器官取少量样本称重并匀浆处理后置于井型γ计数器行99mTc放射性强度检测,通过计算样本与所取器官的质量比得出该器官总放射性强度,最后计算各器官总放射性强度占注射放射性强度的百分比,即得出MWNT-DTPA-99mTc复合物在体内各器官的分布.所有数据使用SPSS13.0软件进行分析。
结果:
1. MWNT-NH2的红外光谱分析,在1580cm-1、3413cm-1分别出现了酰胺和N-H的特征吸收带,证实了MWNT和对苯二胺通过酰胺键连接起来,在MWNT表面引入了氨基。Raman光谱证实MWNT本身在修饰前后结构没有发生改变。此时MWNT溶解性得到初步改善,与水形成黑色溶液,浓度较稀时呈棕色。
2.MWNT-DTPA产物失重量随反应原料比例的增加而增加,结合物DTPA约占总质量的25%;变温磁共振图谱显示产物中的DTPA温度响应性较单体时降低;高分辨透射电镜下可见MWNT表面已被DTPA包裹,其水溶液呈棕色。
3.MWNT-DTPA-99mTc产物在电镜下可见黑色团状金属颗粒稳定连接在MWNT侧壁上,视野内也未发现孤立存在的团状金属颗粒。元素能谱分析显示,金属颗粒中含有Tc和Sn两种元素。
4.与对照组比较,SPECT扫描54分钟内MWNT-DTPA-99mTc组家兔的心脏、肝、脾、肾等器官持续显影,但随时间的延长显影亮度逐渐降低,对以上各器官做时间-放射性曲线可见曲线随时间逐渐下降。随后对尿液离心沉淀物的电镜分析可见有原型MWNT,其表面仍有颗粒附着,元素能谱分析含有Tc元素。
5.定量研究结果显示,注射MWNT-DTPA-99mTc复合物30min时,所测各器官放射性强度之和约占注射总放射性强度的80%以上,其中主要分布于肝脏(≈21%)和肾脏(≈23%),在肺(≈4%)、心脏(≈10%)和脾(≈9%)含量较低,此时已有部分排泄至膀胱(≈11%)。随着时间延长,在1h和2h时肺、心脏、肝脏、脾和肾脏内放射性强度均迅速下降,至终点3h时肺、心脏和脾内放射性已基本消失(<1%),肝脏和肾脏放射性亦明显减少(≈8%),与此同时膀胱内的放射性强度不断增加,至3h时已接近注射总放射性强度的一半(49%)。
结论:
1.成功合成了MWNT-NH2,使MWNT溶解性得到初步改善,并在此基础上完成了MWNT-NH2与DTPA的结合。
2.制备的MWNT-DTPA能够与99mTc成功进行标记。
3.SPECT显像提示,经静脉注射MWNT-DTPA-99mTc后主要分布在心脏、肝脏、脾脏和肾脏,随着时间的延长可缓慢被机体清除,在尿液中发现了以原型排出的MWNT,提示经肾脏排泄可能是主要途径。
4.定量研究证实,经静脉注入MWNT-DTPA-99mTc后主要分布于肺、心脏、肝脏、脾和肾脏等器官,且随时间延续不断减少,膀胱内放射性含量则不断增加,表明99mTc标记的MWNT复合物可经过机体正常代谢并经肾脏途径排出。
Objective
To synthesis amino functionalized multi-walled carbon nanotubes(MWNT) and then used to investigate its vivo metabolism and biodistribution.
Method
1.Amino-functionalized MWNT (MWNT-NH2) was prepared by reacting acyl chloride contained MWNT with Para-phenylenediamine in the presence of pyridine.The resulting MWNT -NH_2 was analysed by infrared spectrum and Raman spectrum.
2.The MWNT-NH_2 was reacted with dianhydride form of diethylenetriaminepentaacetic acid (DTPA) in different proportions. The production was tested by both scanning and transmission electron microscope (SEM,TEM), thermo gravimetric analysis(TGA) and nuclear magnetic resonance(NMR).
3.In the presence of SnCl2, 99mTc was used to chelated with MWNT–DTPA and was analysed by TEM and element spectrum.
4.DTPA ampule was use as control group, MWNT-DTPA-99mTc was iv administered to rabbits, then scanned by single photon emission computed tomography (SPECT). In the end, urine was collected then received TEM and element spectrum analysis.
5. A total of 20 rabbits were used, 5 in each 4 time point. Rabbits were iv administered 1ml MWNT-DTPA-99mTc which contained 0.5mCi of 99mTc activity. At 30min, 1h, 2h and 3h after injection, 5 rabbits per group were killed. Lung, heart, liver, spleen, kidney and bladder(urine included) were collected. Each organ was then weighted and samples were analyzed for 99mTc activity using a well-typeγcounter. Finally, the percentage of radioactivity in each organ was calculated. Statistics was done using SPSS13.0 software.
Result
1.Amide and N-H absorption band showed up at 1580cm-1 and 3413cm-1 in infrared spectrum which means MWNT-NH_2 was successfully prepared. Raman spectrum showed that the structure of MWNT was remaining. The solubility of MWNT increased after this reaction.
2.TGA curve showed that MWNT–DTPA contains 25% of DTPA and its weight loss increased following the material proportion added. NMR illustrated that the DTPA molecular attached on MWNT is much stable than pure DTPA. TEM demonstrated that the MWNT was totally coated by DTPA.
3.Under TEM we could see clearly the black metal particles attaching on MWNT-DTPA surface, Tc and Sn was detected in the particles through element spectrum analysis.
4.Compared with the control group, the MWNT-DTPA-99mTc administered rabbit group continuously visualized mainly in heart, liver, spleen and kidney, but their brightness gradually decreased during 54min, the time-radioactive curve of each organ also descended as time prolonged. TEM and element spectrum analysis of urine samples indicated the abundant presence of prototype MWNT which contains Tc on its surface.
5. Quantitative study showed that the radioactivity in 6 collected organs takes 80% of injected dose, and highly in liver(≈21%) and kidney(≈23%), but lower in lung(≈4%), heart(≈10%) and spleen(≈9%), in bladder the number was about 11%. The number above decreased rapidly in all collected organs as time flows. For example, lung , heart and spleen nearly vanished when liver and kidney remains 8% until 3h after injection. At the same time the bladder takes almost half of the injected dose.
Conclusion
1.MWNT-NH_2 and MWNT-DTPA were successfully synthesized. The solubility of MWNT increased after this functionalization.
2.MWNT-DTPA could be successfully chelated with 99mTc.
3.The iv administered MWNT-DTPA-99mTc mainly distributed in heart, liver, spleen and kidney, but could be cleared from systemic metabolism, for its appearance in urine, the most possible mechanism might be renal excretion route.
4. Quantitative study proved that iv administered MWNT-DTPA-99mTc mainly distributed in lung, heart, liver, spleen and kidney, and decreased as time flows. We also found the radioactivity finally accumulated in bladder which demonstrated that the 99mTc labeled MWNT could be eliminated through renal excretion.
方法:
1.以多壁碳纳米管为原料,通过羧化、酰氯化进而与对苯二胺反应,得到表面有氨基的功能性多壁碳纳米管(MWNT-NH2),对反应前后原料及产物进行红外和Raman光谱分析。
2.将制得的MWNT-NH2与不同比例的二乙烯三胺五乙酸(DTPA)酸酐进行酰胺反应,通过酰胺键共价结合后,得到DTPA修饰的碳纳米管(MWNT-DTPA)并对产物行高分辨电镜、热失重和变温磁共振分析。
3.以蒸馏水溶解MWNT-DTPA,0.01%氯化亚锡(SnCl2)为还原剂,通过螯合作用将99mTc结合在MWNT-DTPA表面,并对产物MWNT-DTPA-99mTc行高分辨电镜及元素能谱分析。
4.以常规DTPA针剂用药为对照组,经耳缘静脉向家兔体内注射MWNT-DTPA-99mTc复合物溶液,同时使用单光子发射计算机断层成像系统(SPECT)扫描,观察其在家兔活体内的代谢及分布情况,随后穿刺膀胱抽取尿液进行电镜分析。
5.进行定量研究时,选取20只家兔随机分为4组,每组5只,麻醉后经耳缘静脉注入1ml配置好的MWNT-DTPA-99mTc复合物溶液,放射性强度0.5mCi。分别在注药物后0.5h、1h、2h和3h将四组家兔处死,取肺、心脏、肝脏、脾、双肾脏和膀胱(含尿)等器官称重,在每种器官取少量样本称重并匀浆处理后置于井型γ计数器行99mTc放射性强度检测,通过计算样本与所取器官的质量比得出该器官总放射性强度,最后计算各器官总放射性强度占注射放射性强度的百分比,即得出MWNT-DTPA-99mTc复合物在体内各器官的分布.所有数据使用SPSS13.0软件进行分析。
结果:
1. MWNT-NH2的红外光谱分析,在1580cm-1、3413cm-1分别出现了酰胺和N-H的特征吸收带,证实了MWNT和对苯二胺通过酰胺键连接起来,在MWNT表面引入了氨基。Raman光谱证实MWNT本身在修饰前后结构没有发生改变。此时MWNT溶解性得到初步改善,与水形成黑色溶液,浓度较稀时呈棕色。
2.MWNT-DTPA产物失重量随反应原料比例的增加而增加,结合物DTPA约占总质量的25%;变温磁共振图谱显示产物中的DTPA温度响应性较单体时降低;高分辨透射电镜下可见MWNT表面已被DTPA包裹,其水溶液呈棕色。
3.MWNT-DTPA-99mTc产物在电镜下可见黑色团状金属颗粒稳定连接在MWNT侧壁上,视野内也未发现孤立存在的团状金属颗粒。元素能谱分析显示,金属颗粒中含有Tc和Sn两种元素。
4.与对照组比较,SPECT扫描54分钟内MWNT-DTPA-99mTc组家兔的心脏、肝、脾、肾等器官持续显影,但随时间的延长显影亮度逐渐降低,对以上各器官做时间-放射性曲线可见曲线随时间逐渐下降。随后对尿液离心沉淀物的电镜分析可见有原型MWNT,其表面仍有颗粒附着,元素能谱分析含有Tc元素。
5.定量研究结果显示,注射MWNT-DTPA-99mTc复合物30min时,所测各器官放射性强度之和约占注射总放射性强度的80%以上,其中主要分布于肝脏(≈21%)和肾脏(≈23%),在肺(≈4%)、心脏(≈10%)和脾(≈9%)含量较低,此时已有部分排泄至膀胱(≈11%)。随着时间延长,在1h和2h时肺、心脏、肝脏、脾和肾脏内放射性强度均迅速下降,至终点3h时肺、心脏和脾内放射性已基本消失(<1%),肝脏和肾脏放射性亦明显减少(≈8%),与此同时膀胱内的放射性强度不断增加,至3h时已接近注射总放射性强度的一半(49%)。
结论:
1.成功合成了MWNT-NH2,使MWNT溶解性得到初步改善,并在此基础上完成了MWNT-NH2与DTPA的结合。
2.制备的MWNT-DTPA能够与99mTc成功进行标记。
3.SPECT显像提示,经静脉注射MWNT-DTPA-99mTc后主要分布在心脏、肝脏、脾脏和肾脏,随着时间的延长可缓慢被机体清除,在尿液中发现了以原型排出的MWNT,提示经肾脏排泄可能是主要途径。
4.定量研究证实,经静脉注入MWNT-DTPA-99mTc后主要分布于肺、心脏、肝脏、脾和肾脏等器官,且随时间延续不断减少,膀胱内放射性含量则不断增加,表明99mTc标记的MWNT复合物可经过机体正常代谢并经肾脏途径排出。
Objective
To synthesis amino functionalized multi-walled carbon nanotubes(MWNT) and then used to investigate its vivo metabolism and biodistribution.
Method
1.Amino-functionalized MWNT (MWNT-NH2) was prepared by reacting acyl chloride contained MWNT with Para-phenylenediamine in the presence of pyridine.The resulting MWNT -NH_2 was analysed by infrared spectrum and Raman spectrum.
2.The MWNT-NH_2 was reacted with dianhydride form of diethylenetriaminepentaacetic acid (DTPA) in different proportions. The production was tested by both scanning and transmission electron microscope (SEM,TEM), thermo gravimetric analysis(TGA) and nuclear magnetic resonance(NMR).
3.In the presence of SnCl2, 99mTc was used to chelated with MWNT–DTPA and was analysed by TEM and element spectrum.
4.DTPA ampule was use as control group, MWNT-DTPA-99mTc was iv administered to rabbits, then scanned by single photon emission computed tomography (SPECT). In the end, urine was collected then received TEM and element spectrum analysis.
5. A total of 20 rabbits were used, 5 in each 4 time point. Rabbits were iv administered 1ml MWNT-DTPA-99mTc which contained 0.5mCi of 99mTc activity. At 30min, 1h, 2h and 3h after injection, 5 rabbits per group were killed. Lung, heart, liver, spleen, kidney and bladder(urine included) were collected. Each organ was then weighted and samples were analyzed for 99mTc activity using a well-typeγcounter. Finally, the percentage of radioactivity in each organ was calculated. Statistics was done using SPSS13.0 software.
Result
1.Amide and N-H absorption band showed up at 1580cm-1 and 3413cm-1 in infrared spectrum which means MWNT-NH_2 was successfully prepared. Raman spectrum showed that the structure of MWNT was remaining. The solubility of MWNT increased after this reaction.
2.TGA curve showed that MWNT–DTPA contains 25% of DTPA and its weight loss increased following the material proportion added. NMR illustrated that the DTPA molecular attached on MWNT is much stable than pure DTPA. TEM demonstrated that the MWNT was totally coated by DTPA.
3.Under TEM we could see clearly the black metal particles attaching on MWNT-DTPA surface, Tc and Sn was detected in the particles through element spectrum analysis.
4.Compared with the control group, the MWNT-DTPA-99mTc administered rabbit group continuously visualized mainly in heart, liver, spleen and kidney, but their brightness gradually decreased during 54min, the time-radioactive curve of each organ also descended as time prolonged. TEM and element spectrum analysis of urine samples indicated the abundant presence of prototype MWNT which contains Tc on its surface.
5. Quantitative study showed that the radioactivity in 6 collected organs takes 80% of injected dose, and highly in liver(≈21%) and kidney(≈23%), but lower in lung(≈4%), heart(≈10%) and spleen(≈9%), in bladder the number was about 11%. The number above decreased rapidly in all collected organs as time flows. For example, lung , heart and spleen nearly vanished when liver and kidney remains 8% until 3h after injection. At the same time the bladder takes almost half of the injected dose.
Conclusion
1.MWNT-NH_2 and MWNT-DTPA were successfully synthesized. The solubility of MWNT increased after this functionalization.
2.MWNT-DTPA could be successfully chelated with 99mTc.
3.The iv administered MWNT-DTPA-99mTc mainly distributed in heart, liver, spleen and kidney, but could be cleared from systemic metabolism, for its appearance in urine, the most possible mechanism might be renal excretion route.
4. Quantitative study proved that iv administered MWNT-DTPA-99mTc mainly distributed in lung, heart, liver, spleen and kidney, and decreased as time flows. We also found the radioactivity finally accumulated in bladder which demonstrated that the 99mTc labeled MWNT could be eliminated through renal excretion.
引文
[1]成会明著,纳米碳管制备、结构、物性及应用,化学工业出版社材料科学与工程出版中心,2002,ISBN 7-5025-3957-3。
[2] Iijima S. Helical microtubules of graphitic carbon, Nature, 1991, 354(6348): 56-58.
[3] Zhou O, Shimoda H, Gao B, etc. Materials Science of Carbon Nanotubes: Fabrication, Integration, and Properties of Macroscopic Structures of Carbon Nanotubes, Acc. Chem. Res., 2002, 35(12): 1045-1053.
[4] Sloan J, Kirkl A I, Hutchison J L, etc. Structural Characterization of Atomically Regulated Nanocrystals Formed within Single-Walled Carbon Nanotubes Using Electron Microscopy, Acc. Chem. Res, 2002, 35(12): 1054-1062.
[5] Kawasaki S, Komatsu K, Okino F, etc. Fluorination of open- and closed-end single-walled carbon nanotubes, Phys. Chem. Chem. Phys., 2004, 6(6): 1769-1772.
[6] Boul P. J, Liu J, Mickelson E, etc. Reversible sidewall functionalization of buckytubes, Chem. Phys. Lett., 1999, 310(3-4): 367-372.
[7] Basiuk E V, Monroy-Pelaez M, Puente-Lee I, etc. Direct Solvent-Free Amination of Closed-Cap Carbon Nanotubes: A Link to Fullerene Chemistry, Nano Lett. 2004, 4(5): 863-866.
[8] Rueckes T, Kim K, Joselevich E, etc. Carbon nanotube-based nonvolatile random access memory for molecular computing, Science, 2000, 289: 94-97.
[9] Pantarotto D, Briand P, Prato M, etc. Translocation of bioactive peptides across cell membranes by carbon nanotubes. Chem Commun,2004,1:16-17.
[10] Georgakilas V, Gournis D, Karakassides M A, etc. Organic derivatization of single-walled carbon nanotubes by clays and intercalated derivatives, Carbon 2004, 42(4): 865-870.
[11] Kooi S E, Schlecht U, Burghard M, etc. Electrochemical modification of single carbon nanotubes, Angew. Chem., Int. Ed., 2002, 41 (8): 1353-1355.
[12] Balasubramanian K, Friedrich M, Jiang C, etc. Electrical transport and confocal Raman studies of electrochemically modified individual carbon nanotubes, Adv. Mater., 2003, 15 (18): 1515-1518.
[13] Balasubramanian K, Sordan R, Burghard M, etc. A selective electrochemical approach to carbon nanotube field-effect transistors, Nano Lett., 2004, 4(5): 827-830.
[14] Carrillo A, Swartz J A, Gamba J M, etc. Noncovalent Functionalization of Graphite and Carbon Nanotubes with Polymer Multilayers and Gold Nanoparticles, Nano Lett., 2003, 3, 1437-1440.
[15] Umek P, Seo J W, Hernadi K, etc. Addition of carbon radicals generated from organic peroxides to single wall carbon nanotubes, Chem. Mater., 2003, 15(25): 4751-4755.
[16] Kónya Z, Vesselenyi I, Niesz K, etc. Large scale production of short functionalized carbon nanotubes, Chem. Phys.Lett., 2002, 360(5–6): 429-435.
[17] Barthos R, Méhn D, Demortier A, etc. Functionalization/Functionalization of single-walled carbon nanotubes by using alkyl-halides, Carbon, 2005, 43: 321-325.
[18] Alberto Bianco, Johan Hoebeke, Kostas Kostarelos. Carbon Nanotubes: On the Road to Deliver;Current Drug Delivery,2005,2,253-259.
[19]蔡建岩;纳米科技发展现状及趋势;长春大学学报; 2005(04):0071-0080.
[20] Manju R, Deependra S, Sara F, etc. Nanocarriers: Promising Vehicle for Bioactive Drugs; Biol. Pharm. Bull,2006,29(9) :1790-1798.
[21] Vasilios G, Nikos T, Davide P, etc. Amino acid functionalisation of water soluble carbon nanotubes; Chem Commun.2002,3050-3051.
[22] Ravi S, Davide P, Lara L, etc. Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers; PNAS February 28,2006 vol103 NO9:3357-3362.
[23] Yi Lin, Shelby Taylor, Huaping Li. Advances toward bioapplications of carbon nanotubes; Jurn Mater Chem.2004,14:527-541.
[24] Leoni L, Desai T. Micromachined biocapsules for cell-based sensing and delivery. Adv Drug Delivery Rev 2004,56:211-229.
[25]李博,廉永福,施祖进,等。单层碳纳米管的化学修饰,高等学校化学学报,2000,21,1631-1635。.
[26] Dubin CH. Special delivery: pharmaceutical companies aim to target their drugs with nano precision. Mech Eng Nanotechnol;2004;126(suppl):10-12.
[27] Kohli A, Alpar H. Potential use of nanoparticles for transcutaneous vaccine delivery:effect of particle size and charge:Int J Pharm 2004;275:13-17.
[28] Yamada T, Ueda M, Seno M, etc. Novel tissue and cell type-specific gene/drug delivery system using surface engineered Hepatitis B virus nano-particles.Curr Drug Targets Infect Disorders 2004,4:163-167.
[29] Brannon-Peppas L, Blanchette J. Nanoparticle and targeted systems for cancer therapy. Adv Drug Delivery Rev 2004,56:1649-1659.
[30]张臣.碳纳米管及其制备技术,微细加工技术.1003-8213,2003, 3:0042-0047.
[31] Ce′dric K, Kostas K, Maurizio P, etc. Functionalized carbon nanotubes as emerging nanovectors for the delivery of therapeutics; Biochimica et Biophysica Acta, 2006,(1758):404-412.
[32] Robert J, Sarunya B, Katerina A, etc. Noncovalent functionalization of carbon nanotubes for highly specific electronic biosensors; PNAS-April 29,2003 ,100(9):4984-4989.
[33] Vasilios G, Nikos T, David P, etc. Amino acid functionalisation of water soluble carbon nanotubes. Chem Commun, 2002, 14,3050–3051.
[34]曹春华,李家麟,贾志杰,等。用二胺在碳纳米管上引入氨基的研究,新型碳材料,2004,6(19):137-140。
[35] Avouris P. Molecular Electronics with Carbon Nanotubes, Acc. Chem. Res., 2002, 35(12) 1026- 1034.
[36] Andrews R, Jacques D, Qian D, etc. Multiwall Carbon Nanotubes: Synthesis and Application, Acc. Chem. Res., 2002, 35(12): 1008-1017.
[37] Niyogi S, Hamon M, Hu H, etc. Chemistry of Single-Walled Carbon Nanotubes, Acc. Chem. Res., 2002, 35(12): 1105-1113.
[38]孙岚,张英鸽,杨留中。纳米活性炭在小鼠体内的分布、存留及淋巴靶向性。军事医学科学院院刊,2005,8(29):349-351.
[39] Charlier J. Defects in Carbon Nanotubes, Acc. Chem. Res., 2002, 35(12): 1063-1069.
[40] Singh R, Pantarotto D, Lacerda L, etc. Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers, PNAS. 2006,103 (9):3357-3362.
[41] Dresselhaus M, Dresselhaus G, Jorio A, etc. Single Nanotube Raman Spectroscopy, Acc. Chem. Res, 2002, 35(12): 1070-1078.
[42] Song W, Kinloch I A, Windle A H. Nematic liquid crystallinity of multiwall carbon nanotubes, Science, 2003, 302, 1363-1363.
[43] Richard C, Balavoine F, Schultz P, etc. Supramolecular self-assembly of lipid derivatives on carbon nanotubes, Science, 2003, 300, 775-778.
[44] Artyukhin A, Bakajin O, Stroeve P, etc. Layer-by-Layer Electrostatic Self-Assembly of Polyelectrolyte Nanoshells on Individual Carbon Nanotube Templates, Langmuir, 2004, 20, 1442-1448.
[45] Liu H, Li S, Zhai J, etc. Self-Assembly of Large-Scale Micropatterns on Aligned Carbon Nanotube Films, Angew. Chem, Int. Ed.2004, 43, 1146-1149.
[46] Sun T, Wang G, Feng L, etc. Reversible Switching between Superhydrophilicity and Superhydrophobicity, Angew. Chem. Int. Ed., 2004, 43, 357-360.
[47] Wang HF, Wang J, Deng X, etc. Biodistribution of single-wall carbon nanotubes in mice. Nanosci Nanotechnol. 2004,4:1019-1024.
[1] Alberto Bianco, Johan Hoebeke, Kostas Kostarelos, etc. Carbon Nanotubes: On the Road to Deliver;Current Drug Delivery,2005,2,253-259.
[2] Kersten G, Crommelin DJ. Carbon nanotubes:on the road to deliver. Vaccine,2003,21: 915-920.
[3] Iijima S. Helical microtubules of graphitic carbon. Nature 1991,354:56-58.
[4] Manju R, Deependra S, Saraf S, etc. Nanocarriers: Promising Vehicle for Bioactive Drugs; Biol. Pharm. Bull. 2006,29(9):1790-1798 .
[5]张臣.碳纳米管及其制备技术,微细加工技术.1003-8213,2003, 3:0042-0047.
[6] Vasilios G, Nikos T, Davide P, etc. Amino acid functionalisation of water soluble carbon nanotubes; Chem Commun.2002,3050-3051.
[7] Tatsis N, Ertl H. Adenoviruses as vaccine vectors. Mol Ther,2004,46(10):616-29.
[8] Yi Lin, Shelby Taylor, Huaping Li, Advances toward bioapplications of carbon nanotubes; Jurn Mater Chem.2004,14:527-541
[9] Leoni L, Desai T. Micromachined biocapsules for cell-based sensing and delivery. Adv Drug Delivery Rev 2004;56:211-229.
[10] Pingang He, Ying Xu, Yuzhi Fang, etc. Applications of Carbon Nanotubes in Electrochemical DNA Biosensors; Microchim Acta,DOI10.2005,1007/s00604-005-0445-1
[11] Dubin C. Special delivery: pharmaceutical companies aim to target their drugs with nano precision. Mech Eng Nanotechnol,2004,126(suppl):10-12.
[12] Kohli A, Alpar H. Potential use of nanoparticles for transcutaneous vaccine delivery:effect of particle size and charge: Int J Pharm 2004,275:13-17.
[13] Yamada T, Ueda M, Seno M. Novel tissue and cell type-specific gene/drug delivery system using surface engineered Hepatitis B virus nano-particles. Curr Drug Targets Infect Disorders 2004,4:163-167.
[14]蔡建岩;纳米科技发展现状及趋势;长春大学学报, 2005,4:0071-0080.
[15] Brannon L, Blanchette J. Nanoparticle and targeted systems for cancer therapy. Adv Drug Delivery Rev 2004;56:1649-59.
[16] Ce′dric K, Kostas K, Maurizio P, etc. Functionalized carbon nanotubes as emerging nanovectors for the delivery of therapeutics; Biochimica Biophysica Acta, 2006,1758: 404-412.
[17] Robert J Chen, Sarunya B, Katerina A, etc. Noncovalent functionalization of carbon nanotubes for highly specific electronic biosensors;PNAS-April,2003,100 (9):4984-4989.
[18] Lee W H, Kim S J, Lee W J, etc. X-ray photoelectron spectroscopic studies of surfacemodified single-walled carbon nanotube material, Appl. Surf. Sci., 2001, 181(1-2): 121-127.
[19] Kamaras K, Itkis M E, Hu H, etc. Covalent Bond Formation to a Carbon Nanotube Metal, Science, 2003, 301(5369): 1501-1501.
[20] Tang DC, De Vit M, Johnston SA. Genetic immunization is a simple method for eliciting an immune response. Nature 1992, 356:152-154.
[21] Hu H, Zhao B, Hamon M A, etc. Sidewall functionalization of single-walled carbon nanotubes by addition of dichlorocarbene, J Am Chem. Soc, 2003, 125 (48): 14893-14900.
[22] Moghaddam M. J, Taylor S, Gao M, etc. Highly Efficient Immobilisation of DNA on the Walls of Carbon Nanotubes Using Photochemistry, Nano Lett, 2004, 4(1): 89-93.
[23] Min Lee K, Li L, Dai L. Asymmetric end-functionalization of multi-walled carbon nanotubes, J. Am. Chem. Soc., 2005, 127 (12): 4122-4123.
[24] Lu X, Tian F, Zhang Q. The [2+1] cycloadditions of dichlorocarbene, silylene, germylene, and oxycarbonylnitrene onto the sidewall of armchair (5, 5) single-wall carbon nanotube, J Phys Chem. 2003, 107 (33): 8388-8391.
[25] Li R, Shang Z, Wang G., etc. Study on dichlorocarbene cycloaddition isomers of armchair single-walled carbon nanotubes, J. mol. struct. Theochem, 2002, 583: 241-247.
[26] Gaal R, Salvetat P, Forro L, etc. Pressure dependence of the resistivity of single-wall carbon nanotube ropes, Phys. Rev. B, 2000, 61(11): 7320-7323.
[27] Kis A, Csanyi G., Salvetat J P, etc. Reinforcement of single-walled carbon nanotube bundles by intertube bridging, Nat. Mater., 2004, 3(3): 153-157.
[28] Gong Y, Liu J, Baskaran S, etc. Surfactant-assisted processing of carbon nanotube/polymer composites, Chem. Mater, 2000, 12 (4): 1049-1052.
[29] Qian D, Dickey C, Andrews R, etc. Load transfer and deformation mechanisms in carbon nanotube-polystyrene composites, Appl. Phys. Lett., 2000, 76(20): 2868-2870.
[30] Shaffer P, Windle A. Fabrication and Characterization of Carbon of Carbon Nanotube/Poly(vinyl alcohol) Composites, Adv. Mater, 1999, 11(11): 937-941.
[2] Iijima S. Helical microtubules of graphitic carbon, Nature, 1991, 354(6348): 56-58.
[3] Zhou O, Shimoda H, Gao B, etc. Materials Science of Carbon Nanotubes: Fabrication, Integration, and Properties of Macroscopic Structures of Carbon Nanotubes, Acc. Chem. Res., 2002, 35(12): 1045-1053.
[4] Sloan J, Kirkl A I, Hutchison J L, etc. Structural Characterization of Atomically Regulated Nanocrystals Formed within Single-Walled Carbon Nanotubes Using Electron Microscopy, Acc. Chem. Res, 2002, 35(12): 1054-1062.
[5] Kawasaki S, Komatsu K, Okino F, etc. Fluorination of open- and closed-end single-walled carbon nanotubes, Phys. Chem. Chem. Phys., 2004, 6(6): 1769-1772.
[6] Boul P. J, Liu J, Mickelson E, etc. Reversible sidewall functionalization of buckytubes, Chem. Phys. Lett., 1999, 310(3-4): 367-372.
[7] Basiuk E V, Monroy-Pelaez M, Puente-Lee I, etc. Direct Solvent-Free Amination of Closed-Cap Carbon Nanotubes: A Link to Fullerene Chemistry, Nano Lett. 2004, 4(5): 863-866.
[8] Rueckes T, Kim K, Joselevich E, etc. Carbon nanotube-based nonvolatile random access memory for molecular computing, Science, 2000, 289: 94-97.
[9] Pantarotto D, Briand P, Prato M, etc. Translocation of bioactive peptides across cell membranes by carbon nanotubes. Chem Commun,2004,1:16-17.
[10] Georgakilas V, Gournis D, Karakassides M A, etc. Organic derivatization of single-walled carbon nanotubes by clays and intercalated derivatives, Carbon 2004, 42(4): 865-870.
[11] Kooi S E, Schlecht U, Burghard M, etc. Electrochemical modification of single carbon nanotubes, Angew. Chem., Int. Ed., 2002, 41 (8): 1353-1355.
[12] Balasubramanian K, Friedrich M, Jiang C, etc. Electrical transport and confocal Raman studies of electrochemically modified individual carbon nanotubes, Adv. Mater., 2003, 15 (18): 1515-1518.
[13] Balasubramanian K, Sordan R, Burghard M, etc. A selective electrochemical approach to carbon nanotube field-effect transistors, Nano Lett., 2004, 4(5): 827-830.
[14] Carrillo A, Swartz J A, Gamba J M, etc. Noncovalent Functionalization of Graphite and Carbon Nanotubes with Polymer Multilayers and Gold Nanoparticles, Nano Lett., 2003, 3, 1437-1440.
[15] Umek P, Seo J W, Hernadi K, etc. Addition of carbon radicals generated from organic peroxides to single wall carbon nanotubes, Chem. Mater., 2003, 15(25): 4751-4755.
[16] Kónya Z, Vesselenyi I, Niesz K, etc. Large scale production of short functionalized carbon nanotubes, Chem. Phys.Lett., 2002, 360(5–6): 429-435.
[17] Barthos R, Méhn D, Demortier A, etc. Functionalization/Functionalization of single-walled carbon nanotubes by using alkyl-halides, Carbon, 2005, 43: 321-325.
[18] Alberto Bianco, Johan Hoebeke, Kostas Kostarelos. Carbon Nanotubes: On the Road to Deliver;Current Drug Delivery,2005,2,253-259.
[19]蔡建岩;纳米科技发展现状及趋势;长春大学学报; 2005(04):0071-0080.
[20] Manju R, Deependra S, Sara F, etc. Nanocarriers: Promising Vehicle for Bioactive Drugs; Biol. Pharm. Bull,2006,29(9) :1790-1798.
[21] Vasilios G, Nikos T, Davide P, etc. Amino acid functionalisation of water soluble carbon nanotubes; Chem Commun.2002,3050-3051.
[22] Ravi S, Davide P, Lara L, etc. Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers; PNAS February 28,2006 vol103 NO9:3357-3362.
[23] Yi Lin, Shelby Taylor, Huaping Li. Advances toward bioapplications of carbon nanotubes; Jurn Mater Chem.2004,14:527-541.
[24] Leoni L, Desai T. Micromachined biocapsules for cell-based sensing and delivery. Adv Drug Delivery Rev 2004,56:211-229.
[25]李博,廉永福,施祖进,等。单层碳纳米管的化学修饰,高等学校化学学报,2000,21,1631-1635。.
[26] Dubin CH. Special delivery: pharmaceutical companies aim to target their drugs with nano precision. Mech Eng Nanotechnol;2004;126(suppl):10-12.
[27] Kohli A, Alpar H. Potential use of nanoparticles for transcutaneous vaccine delivery:effect of particle size and charge:Int J Pharm 2004;275:13-17.
[28] Yamada T, Ueda M, Seno M, etc. Novel tissue and cell type-specific gene/drug delivery system using surface engineered Hepatitis B virus nano-particles.Curr Drug Targets Infect Disorders 2004,4:163-167.
[29] Brannon-Peppas L, Blanchette J. Nanoparticle and targeted systems for cancer therapy. Adv Drug Delivery Rev 2004,56:1649-1659.
[30]张臣.碳纳米管及其制备技术,微细加工技术.1003-8213,2003, 3:0042-0047.
[31] Ce′dric K, Kostas K, Maurizio P, etc. Functionalized carbon nanotubes as emerging nanovectors for the delivery of therapeutics; Biochimica et Biophysica Acta, 2006,(1758):404-412.
[32] Robert J, Sarunya B, Katerina A, etc. Noncovalent functionalization of carbon nanotubes for highly specific electronic biosensors; PNAS-April 29,2003 ,100(9):4984-4989.
[33] Vasilios G, Nikos T, David P, etc. Amino acid functionalisation of water soluble carbon nanotubes. Chem Commun, 2002, 14,3050–3051.
[34]曹春华,李家麟,贾志杰,等。用二胺在碳纳米管上引入氨基的研究,新型碳材料,2004,6(19):137-140。
[35] Avouris P. Molecular Electronics with Carbon Nanotubes, Acc. Chem. Res., 2002, 35(12) 1026- 1034.
[36] Andrews R, Jacques D, Qian D, etc. Multiwall Carbon Nanotubes: Synthesis and Application, Acc. Chem. Res., 2002, 35(12): 1008-1017.
[37] Niyogi S, Hamon M, Hu H, etc. Chemistry of Single-Walled Carbon Nanotubes, Acc. Chem. Res., 2002, 35(12): 1105-1113.
[38]孙岚,张英鸽,杨留中。纳米活性炭在小鼠体内的分布、存留及淋巴靶向性。军事医学科学院院刊,2005,8(29):349-351.
[39] Charlier J. Defects in Carbon Nanotubes, Acc. Chem. Res., 2002, 35(12): 1063-1069.
[40] Singh R, Pantarotto D, Lacerda L, etc. Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers, PNAS. 2006,103 (9):3357-3362.
[41] Dresselhaus M, Dresselhaus G, Jorio A, etc. Single Nanotube Raman Spectroscopy, Acc. Chem. Res, 2002, 35(12): 1070-1078.
[42] Song W, Kinloch I A, Windle A H. Nematic liquid crystallinity of multiwall carbon nanotubes, Science, 2003, 302, 1363-1363.
[43] Richard C, Balavoine F, Schultz P, etc. Supramolecular self-assembly of lipid derivatives on carbon nanotubes, Science, 2003, 300, 775-778.
[44] Artyukhin A, Bakajin O, Stroeve P, etc. Layer-by-Layer Electrostatic Self-Assembly of Polyelectrolyte Nanoshells on Individual Carbon Nanotube Templates, Langmuir, 2004, 20, 1442-1448.
[45] Liu H, Li S, Zhai J, etc. Self-Assembly of Large-Scale Micropatterns on Aligned Carbon Nanotube Films, Angew. Chem, Int. Ed.2004, 43, 1146-1149.
[46] Sun T, Wang G, Feng L, etc. Reversible Switching between Superhydrophilicity and Superhydrophobicity, Angew. Chem. Int. Ed., 2004, 43, 357-360.
[47] Wang HF, Wang J, Deng X, etc. Biodistribution of single-wall carbon nanotubes in mice. Nanosci Nanotechnol. 2004,4:1019-1024.
[1] Alberto Bianco, Johan Hoebeke, Kostas Kostarelos, etc. Carbon Nanotubes: On the Road to Deliver;Current Drug Delivery,2005,2,253-259.
[2] Kersten G, Crommelin DJ. Carbon nanotubes:on the road to deliver. Vaccine,2003,21: 915-920.
[3] Iijima S. Helical microtubules of graphitic carbon. Nature 1991,354:56-58.
[4] Manju R, Deependra S, Saraf S, etc. Nanocarriers: Promising Vehicle for Bioactive Drugs; Biol. Pharm. Bull. 2006,29(9):1790-1798 .
[5]张臣.碳纳米管及其制备技术,微细加工技术.1003-8213,2003, 3:0042-0047.
[6] Vasilios G, Nikos T, Davide P, etc. Amino acid functionalisation of water soluble carbon nanotubes; Chem Commun.2002,3050-3051.
[7] Tatsis N, Ertl H. Adenoviruses as vaccine vectors. Mol Ther,2004,46(10):616-29.
[8] Yi Lin, Shelby Taylor, Huaping Li, Advances toward bioapplications of carbon nanotubes; Jurn Mater Chem.2004,14:527-541
[9] Leoni L, Desai T. Micromachined biocapsules for cell-based sensing and delivery. Adv Drug Delivery Rev 2004;56:211-229.
[10] Pingang He, Ying Xu, Yuzhi Fang, etc. Applications of Carbon Nanotubes in Electrochemical DNA Biosensors; Microchim Acta,DOI10.2005,1007/s00604-005-0445-1
[11] Dubin C. Special delivery: pharmaceutical companies aim to target their drugs with nano precision. Mech Eng Nanotechnol,2004,126(suppl):10-12.
[12] Kohli A, Alpar H. Potential use of nanoparticles for transcutaneous vaccine delivery:effect of particle size and charge: Int J Pharm 2004,275:13-17.
[13] Yamada T, Ueda M, Seno M. Novel tissue and cell type-specific gene/drug delivery system using surface engineered Hepatitis B virus nano-particles. Curr Drug Targets Infect Disorders 2004,4:163-167.
[14]蔡建岩;纳米科技发展现状及趋势;长春大学学报, 2005,4:0071-0080.
[15] Brannon L, Blanchette J. Nanoparticle and targeted systems for cancer therapy. Adv Drug Delivery Rev 2004;56:1649-59.
[16] Ce′dric K, Kostas K, Maurizio P, etc. Functionalized carbon nanotubes as emerging nanovectors for the delivery of therapeutics; Biochimica Biophysica Acta, 2006,1758: 404-412.
[17] Robert J Chen, Sarunya B, Katerina A, etc. Noncovalent functionalization of carbon nanotubes for highly specific electronic biosensors;PNAS-April,2003,100 (9):4984-4989.
[18] Lee W H, Kim S J, Lee W J, etc. X-ray photoelectron spectroscopic studies of surfacemodified single-walled carbon nanotube material, Appl. Surf. Sci., 2001, 181(1-2): 121-127.
[19] Kamaras K, Itkis M E, Hu H, etc. Covalent Bond Formation to a Carbon Nanotube Metal, Science, 2003, 301(5369): 1501-1501.
[20] Tang DC, De Vit M, Johnston SA. Genetic immunization is a simple method for eliciting an immune response. Nature 1992, 356:152-154.
[21] Hu H, Zhao B, Hamon M A, etc. Sidewall functionalization of single-walled carbon nanotubes by addition of dichlorocarbene, J Am Chem. Soc, 2003, 125 (48): 14893-14900.
[22] Moghaddam M. J, Taylor S, Gao M, etc. Highly Efficient Immobilisation of DNA on the Walls of Carbon Nanotubes Using Photochemistry, Nano Lett, 2004, 4(1): 89-93.
[23] Min Lee K, Li L, Dai L. Asymmetric end-functionalization of multi-walled carbon nanotubes, J. Am. Chem. Soc., 2005, 127 (12): 4122-4123.
[24] Lu X, Tian F, Zhang Q. The [2+1] cycloadditions of dichlorocarbene, silylene, germylene, and oxycarbonylnitrene onto the sidewall of armchair (5, 5) single-wall carbon nanotube, J Phys Chem. 2003, 107 (33): 8388-8391.
[25] Li R, Shang Z, Wang G., etc. Study on dichlorocarbene cycloaddition isomers of armchair single-walled carbon nanotubes, J. mol. struct. Theochem, 2002, 583: 241-247.
[26] Gaal R, Salvetat P, Forro L, etc. Pressure dependence of the resistivity of single-wall carbon nanotube ropes, Phys. Rev. B, 2000, 61(11): 7320-7323.
[27] Kis A, Csanyi G., Salvetat J P, etc. Reinforcement of single-walled carbon nanotube bundles by intertube bridging, Nat. Mater., 2004, 3(3): 153-157.
[28] Gong Y, Liu J, Baskaran S, etc. Surfactant-assisted processing of carbon nanotube/polymer composites, Chem. Mater, 2000, 12 (4): 1049-1052.
[29] Qian D, Dickey C, Andrews R, etc. Load transfer and deformation mechanisms in carbon nanotube-polystyrene composites, Appl. Phys. Lett., 2000, 76(20): 2868-2870.
[30] Shaffer P, Windle A. Fabrication and Characterization of Carbon of Carbon Nanotube/Poly(vinyl alcohol) Composites, Adv. Mater, 1999, 11(11): 937-941.